Signals transduced by the B cell receptor (BCR) regulate B cell tolerance to self-antigens by controlling clonal deletion, receptor editing and anergy. BCR signals that mediate B cell tolerance are not fully understood, and altered BCR signaling that elicits the breakdown of B cell tolerance and consequent autoimmune disease is even less well understood. Stimulation of phospholipase C? (PLC?), a lipid enzyme critical for BCR signaling, generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) that activate the PKC and Ca2+/ calcineurin pathways, respectively. PLC? has two isoforms, PLC?1 and PLC?2. Previously, we reported a key role for the PLC?2-mediated PKC/Bcl10/TAK1/IKK/NF-kB signaling pathway in B cell maturation and activation, immunoglobulin light chain locus activation, and BCR receptor editing. As PLC?1 deficiency causes early embryonic death, we generated conditional PLC?1 knockout mice, and discovered that B cell-specific deletion of PLC?1 impairs BCR signaling and precludes the maintenance of B cell anergy in these mice. These new data reveal a pivotal yet under-appreciated role for PLC?1 in the establishment of self-tolerance. The clinical relevance of these findings is that PLCg? mutations alter BCR signaling and elicit immunodeficiency and autoimmune diseases in human patients. Thus, the PLC? pathway plays an essential role in controlling B cell tolerance in both mice and humans. The primary objective of this renewal application is to study the molecular mechanism by which the PLC?-dependent pathway converts a small quantitative change in BCR signaling into qualitative changes in B cells that drives them into a state of anergy. Specifically, we will 1) determine the molecular mechanism by which PLC?1 regulates B cell anergy, and 2) study how a novel molecule controls PLC? and its downstream pathways to regulate B cell anergy. This mechanism-based research will conceptually advance our understanding of the molecular signaling mechanism by which self- antigens regulate B cell anergy. Novel insight into the molecular pathogenesis of human autoimmune disease may identify novel target therapeutics for certain of these diseases.